Insulin-like Growth Factor Binding Protein-3 Research Articles

Taurine ameliorates cellular senescence associated with an increased hydrogen sulfide and a decreased hepatokine, IGFBP-1, in CCl4-induced hepatotoxicity in mice.

Taurine ameliorates cellular senescence associated with an increased hydrogen sulfide and a decreased hepatokine, IGFBP-1, in CCl4-induced hepatotoxicity in mice.

Controllable nickel ions release from deferoxamine mesylate-triggered nickel-iron layered double hydroxide for eliciting apoptotic cell death in prostate cancer

Despite their unique advantages and vast potential, nanomaterials employed in cancer therapy still encounter challenges such as uneven biodistribution, unintended drug leakage, and especially potential tissue damage caused by off-target toxicity. Bioinert nanomaterials, known for their excellent chemical stability, and minimal biological reactivity, can exert localized tumoricidal effects in response to specific external stimuli. However, the lack of precise control or poor penetration depth largely limits the therapeutic efficacy, necessitating the development of innovative stimuli-responsive therapeutic strategies. This study presents an alternative drug-responsive cancer therapeutic approach based on nickel-iron layered double hydroxide (NiFe-LDH), which exhibited negligible toxicity to both normal cells and cancer cells. By conjugating a platelet-derived growth factor receptor (PDGFR)-β-targeting cyclic peptide, NiFe-LDH achieved high specificity for prostate cancer cells, significantly enhancing tumor targeting and accumulation. Upon administration of deferoxamine mesylate (DFOM), an FDA-approved iron chelator, NiFe-LDH transitioned from a “bioinert” state to a “bioactive” nanotherapeutic through structural disassembly and robust release of nickel ions (Ni²⁺). The released ions disrupted mitochondrial function, upregulated insulin-like growth factor binding protein 3 (IGFBP3), and further inhibited the PI3K/AKT/mTOR signaling pathway, consequently leading to potent and selective induction of apoptosis in prostate cancer cells. Unlike conventional therapies, which often cause varying degrees of toxicity in non-target organs, this stimuli-responsive nanoplatform could minimize off-target effects and systemic toxicity by combining the non-toxic LDH with the clinically used DFOM. Our findings demonstrate that DFOM-responsive NiFe-LDH can effectively inhibit tumor growth in both cultured cells and tumor xenografts, suggesting a rational and clinically translatable platform for precision cancer therapy.Graphical

IGFBP5 promotes EndoMT and renal fibrosis through H3K18 lactylation in diabetic nephropathy

ObjectiveDiabetic nephropathy (DN) is an important complication in diabetic patients that severely impacts their quality of life and life expectancy. Although metabolic and inflammatory responses induced by hyperglycemia are considered the primary pathogenic factors of DN, the specific molecular mechanisms involved remain unclear. Here, we investigated the role of insulin-like growth factor-binding protein 5 (IGFBP5) in DN using in vitro cell experiments and mouse models.MethodsWe assessed the effects of high-glucose conditions on IGFBP5 expression in glomerular endothelial cells and evaluated its regulatory effects on glycolysis, NLRP3 inflammasome activation, endothelial‒mesenchymal transition (EndoMT), and histone lactylation via the suppression of IGFBP5. Furthermore, we evaluated the effects of IGFBP5 on renal fibrosis and confirmed its regulatory mechanisms in DN model mice.ResultsKnockdown of IGFBP5 inhibited high glucose-induced EndoMT in glomerular endothelial cells, which could also be suppressed by the NLRP3 inflammasome inhibitor MCC950. In addition, silencing of IGFBP5 decreased glycolytic activity and histone lactylation, thereby inhibiting the activation of the NLRP3 inflammasome and EndoMT. Furthermore, in mouse models of DN, IGFBP5 knockdown alleviated renal fibrosis and reduced glycolysis, histone lactylation, NLRP3 inflammasome activation and EndoMT.ConclusionsIGFBP5 promotes NLRP3 inflammasome-induced EndoMT and renal fibrosis by regulating glycolysis-mediated histone lactylation, accelerating the progression of DN. These findings provide a new potential therapeutic target for DN.

IGFBP-2 and IGF-II: Key Components of the Neural Stem Cell Niche? Implications for Glioblastoma Pathogenesis.

Glioblastoma is a fatal and aggressive cancer with no cure. It is becoming increasingly clear that glioblastoma initiation is a result of adult neural stem cell (NSC) transformation-most likely those within the subventricular zone (SVZ). Indeed, transcriptomic analysis indicates that glioblastomas are reminiscent of a neurodevelopmental hierarchy, in which neural stem and progenitor markers are widely expressed by tumour stem-like cells. However, NSC fates and the cues that drive them are poorly understood. Studying the crosstalk within NSC niches may better inform our understanding of glioblastoma initiation and development. Insulin-like growth factor binding protein 2 (IGFBP-2) has a well-established prognostic role in glioblastoma, and cell-based mechanistic studies show the independent activation of downstream oncogenic pathways. However, IGFBP-2 is more commonly recognised as a modulator of insulin-like growth factors (IGFs) for receptor tyrosine kinase signal propagation or attenuation. In the adult human brain, both IGFBP-2 and IGF-II expression are retained in the choroid plexus (ChP) and secreted into the cerebral spinal fluid (CSF). Moreover, secretion by closely associated cells and NSCs themselves position IGFBP-2 and IGF-II as interesting factors within the NSC niche. In this review, we will highlight the experimental findings that show IGFBP-2 and IGF-II influence NSC behaviour. Moreover, we will link this to glioblastoma biology and demonstrate the requirement for further analysis of these factors in glioma stem cells (GSCs).

Pilot Investigation on Markers of Bone Metabolism, Angiogenesis, and Neuroendocrine Activity as Potential Predictors of Survival of Metastatic Prostate Cancer Patients with Bone Metastases.

Prostate cancer with bone metastasis exhibits significant heterogeneity, complicating prognosis, and treatment. This study explores the potential of plasma, serum, and urine biomarkers to stratify patients and evaluate their prognostic value. Using two-step clustering, we analyzed baseline levels of Platelet-derived growth factor-BB (PDGF-BB), Insulin-like growth factor-binding protein 1 (IGFBP-1), Bone Morphogenetic Protein 2 (BMP-2), Vascular endothelial growth factor (VEGF) (plasma and urine), prostate-specific antigen (PSA), neuron-specific enolase (NSE), chromogranin A (CgA) and bone-specific alkaline phosphatase (BAP) (serum) and creatinine (Cr), and type I collagen-cross-linked N telopeptide (NTx) (urine) in 29 patients with prostate cancer and bone metastasis. Longitudinal biomarker dynamics were assessed at baseline, 6 months, and 12 months. Clinical outcomes were evaluated using Kaplan-Meier and multivariate analyses. Three distinct groups (C1, C2, and C3) were identified. C1 exhibited elevated pPDGF-BB and pVEGF levels, C3 had increased pBAP and uNTx/Cr, and C2 showed lower biomarker levels. Prior treatments influenced biomarker levels, with bisphosphonates reducing bone turnover markers and radiotherapy correlating with long-term changes in growth factors. Longitudinal analysis revealed unique biomarker dynamics within each group, with a tendency for pPDGF-BB and pVEGF levels to decrease over time in C1, and distinct trends in uNTx/Cr between groups. Despite individual biomarkers failing to predict survival, C3 patients demonstrated significantly worse survival than C1 and C2. Molecular clustering of peripheral blood and urinary biomarkers identifies distinct subgroups with metastatic castration-resistant prostate cancer patients outperforming traditional models in outcome prediction and supporting its potential for personalized treatment and prognosis.

Liver portal fibroblasts induce the functions of primary human hepatocytes in vitro

In vitro human liver models are critical to mitigate species-specific differences observed for toxicology, disease modeling, and regenerative medicine. Interactions with mesenchyme (i.e., fibroblasts) can promote phenotypic functions of primary human hepatocytes (PHHs) in culture; however, using liver-derived fibroblasts remains elusive. Portal fibroblasts (PFs) around the portal triad influence bile duct formation during development, but their role in regulating homeostatic hepatic functions remains unknown. Here, we show that human liver PFs induce long-term phenotypic functions in PHHs at higher levels than activated hepatic stellate cells across 2-dimensional and 3-dimensional culture formats. While PF-conditioned media induces some hepatic functions, partly via insulin-like growth factor binding protein-5 signaling, direct contact is necessary to induce optimal functional levels. Inhibiting Notch signaling reduces progenitor-like characteristics of PHHs and further enhances functionality. Overall, this work demonstrates a unique role for PFs in modulating hepatic functions and provides all-human and all-liver coculture strategies for downstream applications.

STMN1–IGFBP5 axis induces senescence and extracellular matrix degradation in nucleus pulposus cells: In vivo and in vitro insights

Cellular dysfunction induced by senescent nucleus pulposus (NP) cells is a key factor in the pathogenesis of intervertebral disc degeneration (IDD). Stathmin 1 (STMN1) has been proposed as a telomere-associated senescence marker implicated in senescence in many age-related diseases. Nevertheless, its role in NP cell senescence remains unclear. This study revealed that STMN1 was significantly upregulated in human degenerative and naturally aged rat NP tissue specimens. In vitro models demonstrated that STMN1 expression levels were elevated in replicative and TNF-α-induced NP senescence models. Lentiviral knockdown of STMN1 inhibited NP cell senescence, while overexpression promoted NP cell senescence, along with extracellular matrix (ECM) degradation. An in-depth mechanism indicated that insulin-like growth factor-binding protein 5 (IGFBP5), a downstream pro-senescence gene of STMN1, can induce NP cellular senescence and ECM degradation following its upregulation by STMN1. Furthermore, STMN1 knockdown reduced IGFBP5 expression and mitigated IDD development in a rat model of caudal discs puncture-induced IDD. Combined with the abovementioned results, we demonstrated for the first time that the STMN1–IGFBP5 axis can induce NP cell senescence and ECM degradation, thereby accelerating IDD development. This provides a robust foundation for the development of molecular-targeted therapies for IDD.

Aregs-IGFBP3-mediated SMC-like cells apoptosis impairs beige adipocytes formation in aged mice.

Aging is associated with a decline in the browning capacity of white adipose tissue (WAT), contributing to metabolic dysfunction. Beige adipocytes, which dissipate excess energy as heat, are a key feature of this process. In this study, we investigate the role of adipose stem and progenitor cells (ASPCs), specifically the Aregs (CD142+) subpopulation, in regulating beige adipocyte formation in aged mice under cold stimulation. Our findings reveal that Aregs significantly increase in the subcutaneous WAT (sWAT) of aged mice following cold exposure. We further demonstrate that Aregs secrete insulin-like growth factor binding protein 3 (IGFBP3), which appears to play a pivotal role in the cross-talk between adipogenesis-regulatory cells (Aregs) and smooth muscle cell-like (SMC-like) cells, thereby leading to the inhibition of beige adipocytes formation. Functional enrichment analysis highlighted the activation of TGFβ, MAPK and p53 signaling pathways in SMC-like cells, all of which are known to induce cell apoptosis and fibrosis. Moreover, IGFBP3 was found to interact with receptors and signaling molecules, including Egfr, Irf1 and Cdkn1a, in SMC-like cells, enhancing their apoptosis. Co-culture experiments confirmed that IGFBP3 significantly suppressed the formation of beige adipocytes, further corroborating its role in impairing browning. Overall, our study provides novel insights into the molecular mechanisms by which Aregs and IGFBP3 contribute to the age-related decline in WAT browning. These findings suggest potential therapeutic targets for reversing impaired WAT browning in aging and related metabolic disorders.

The impact of soft contact lenses on the corneal neuromediators and optical quality in high myopia.

The impact of soft contact lenses on the corneal neuromediators and optical quality in high myopia.

Targeting miR-103a-3p/IGFBP5 axis: a potential therapeutic strategy for gastric cancer progression

Gastric cancer is a significant contributor to worldwide cancer deaths with limited treatment options and poor patient survival. MicroRNAs play crucial roles as potential oncogenic factors or tumor suppressors in cancers by modulating cell cycle progression, proliferation, migration, invasion, and apoptosis. However, the functional implications of miR-103a-3p in gastric cancer remain poorly known. The current study demonstrates a noteworthy increase in the expression of miR-103a-3p in gastric cancer tissues when compared to neighboring non-cancerous tissues. Our functional investigations indicate that the upregulation of miR-103a-3p contributes to enhanced proliferation, invasion, and migration capabilities in gastric cancer cells. After mechanistic studies, our findings indicate that miR-103a-3p may directly target insulin-like growth factor binding protein 5 (IGFBP5) in gastric cancer. Moreover, rescue experiments reveal that IGFBP5 overexpression can attenuate the progression induced by miR-103a-3p in gastric cancer cells. In summary, our findings suggest that the miR-103a-3p/IGFBP5 axis may play a role in gastric cancer progression, highlighting its potential as a therapeutic target and prognostic marker.

Abstract 4936: The association between plasma IGFBP7 and cancer incidence, cancer mortality, and all-cause mortality in ARIC

Abstract Background: Insulin-like Growth Factor Binding Protein 7 (IGFBP7) may modulate IGF signaling and influence non-IGF molecular mechanisms. We analyzed whether IGFBP7 concentration in plasma is associated with risk of cancer incidence, cancer mortality, and all-cause mortality. Methods: We conducted a prospective cohort analysis of 10, 834 participants (54.8% female, 24.3% Black) with no cancer history for cancer incidence and mortality analyses, and 11, 761 participants (55.6% female, 23.6% Black) for the all-cause mortality analysis in the Atherosclerosis Risk in Communities study. The median follow-up time was 22.8, 23.5, and 25.6 years for the respective analyses. Participants were aged 46-70 years old at start of follow-up. Plasma IGFBP7 was measured using SomaScan® 5K assay, an aptamer-based technology for protein profiling. Incident cancer diagnoses were ascertained by state cancer registry linkage supplemented with medical records and death certificates. Mortality was ascertained by death certificates, including via the National Death Index. We estimated the association between IGFBP7 plasma levels (log2transformed) and outcomes including cancer incidence, cancer mortality, and all-cause mortality using Cox proportional hazards regression models adjusting for age, sex, race, and other potential risk factors for cancer and/or mortality. Results: The association between IGFBP7 and total cancer incidence (3, 347 cases, 200, 279 person-years) was null (HR=0.99, 95% CI 0.85-1.16). However, IGFBP7 was positively associated with lung cancer incidence (479 cases, 199, 823 person-years; HR=1.40, 95% CI 0.93-2.10), unlike for other common cancer sites. The association between IGFBP7 and total cancer mortality (1, 420 deaths, 222, 320 person-years) was statistically significant (HR=1.39, 95% CI 1.10-1.76). Of the common cancers, IGFBP7 was positively associated with lung cancer mortality (HR=1.69, 95% CI 1.10-2.60) and breast cancer mortality (HR=2.09, 95% CI 0.88-4.97). The association between IGFBP7 and all-cause mortality (6, 981 deaths, 262, 734 person-years) was statistically significant and the strongest among the three main analyses (HR=1.72, 95% CI 1.55-1.91). Stratifying by age, the strongest association between IGFBP7 and all-cause mortality was in the youngest age quartile (ages 46.9-52.6 years; HR=2.69, 95% CI 2.01-3.59). IGFBP7 is not strongly correlated with IGF-1 and other family proteins. Conclusions: High circulating IGFBP7 levels may be a risk factor for cancer and all-cause mortality, especially among those in middle adulthood. High circulating IGFBP7 levels may also be a risk factor for both lung cancer incidence and mortality. Additional research and laboratory testing will be necessary to determine whether IGFBP7’s influence on IGF signaling or other mechanisms contribute to tumor progression and mortality, in general. Support: NHLBI, NCI, NPCR Citation Format: Vernon A. Burk, Michael N. Pollak, Corinne E. Joshu, Anna Prizment, Elizabeth A. Platz. The association between plasma IGFBP7 and cancer incidence, cancer mortality, and all-cause mortality in ARIC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4936.

Abstract 7067: Integrating blood-based biomarkers and RNA-Seq Data for enhanced colorectal cancer screening

Abstract Colorectal cancer (CRC) is the second cause of cancer-related deaths in the United States and the first leading cause for Puerto Rican Hispanics (PRH). Despite its preventability through screening, compliance still needs to improve due to the invasiveness of current tools. There is a growing demand for validated molecular biomarker panels for minimally invasive blood-based CRC screening. This study evaluated the diagnostic accuracy of four promising blood-based biomarkers and incorporated RNA-seq data from an independent cohort to provide biological insights into biomarker performance. A retrospective case-control study was conducted in plasma samples from 124 CRC cases and 124 age- and sex-matched controls recruited through the Puerto Rico Familial Colorectal Cancer Registry (PURIFICAR). Biomarkers tested included methylated DNA encoding the Septin-9 gene (mSEPT9) using Epi proColon® 2.0 CE, insulin-like growth factor binding protein 2 (IGFBP2), dickkopf-3 (DKK3), and pyruvate kinase M2 (PKM2) by ELISA. Diagnostic accuracy was measured using the receiver operating characteristic (ROC) area under the curve (AUC) and sensitivity and specificity. For the RNA-seq (Illumina) assay, a case-case study was performed on 15 tumor and 15 adjacent mucosa samples from 7 early and 8 advanced-stage CRC cases. Differentially expressed genes (DEGs) with an adjusted p-value < 0.05 were identified between tumor and adjacent mucosa across stages. Pathway enrichment was performed using Gene Set Enrichment Analysis (GSEA) and KEGG databases. Biomarkers and gene expression patterns were cross-validated to identify shared pathways. Diagnostic accuracy for individual biomarkers mSEPT9, IGFBP2, DKK3, and PKM2 was 62.9%, 69.7%, 61.6%, and 50.8%, respectively. Combined biomarkers AUC was of 74.4%, outperforming all individual markers except IGFBP2 in advanced-stage CRC. RNA-seq identified 481 DEGs unique to early-stage and 849 to advanced-stage CRC. Genes DKK3 and PKM2, were differentially expressed in both stages. Additionally, DKK1 and DKK2, were uniquely upregulated in early-stage tumors. Dysregulation of Wnt signaling, PI3K-Akt signaling, and cytokine-cytokine receptor interaction pathways were observed across stages. Our results show that integrating plasma biomarker analysis with RNA-seq data enables the identification of critical shared pathways, supporting the utility of a multi-omics approach for CRC screening. Plasma biomarkers demonstrated promising diagnostic accuracy, with IGFBP2 as the most accurate individual marker across CRC stages. The differential expression of DKK1 and DKK2 in early-stage tumors highlights their potential as early CRC biomarkers, warranting validation in plasma samples. These findings support the development of minimally invasive blood-based screening tools for CRC, offering a promising strategy for early detection and improved patient outcomes for PRH. Citation Format: Elba V. Caraballo-Rivera, Hilmaris Centeno-Girona, Camille Zenón-Meléndez, Sheila López -Acevedo, Brenda Torres-Velásquez, Josue Pérez-Santiago, Madeline M. Martir-Ocasio, Maria González-Pons, Marcia R. Cruz-Correa. Integrating blood-based biomarkers and RNA-Seq Data for enhanced colorectal cancer screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7067.

Proteomic signatures for fibrosis in MASLD: a biopsy-proven dual-cohort study

Objectives Predicting disease progression in metabolic dysfunction-associated steatotic liver disease (MASLD) is challenging, and current non-invasive tests (NITs) lack the precision to replace liver biopsy. This study aimed to identify plasma biomarkers for different stages of fibrosis using affinity-based proteomics in two biopsy-proven cohorts. The primary objective was to identify biomarkers capable of distinguishing between low-to-no fibrosis (F0-1) and significant fibrosis (F2-4) in MASLD. Materials and methods Participants in the discovery cohort were recruited from Uppsala University Hospital and Swedish CArdioPulmonary bioImage Study (SCAPIS), while the validation cohort was included from Linköping University Hospital. All participants diagnosed with MASLD underwent liver biopsy and were categorized by fibrosis stage (F0-1 or F2-4). A total of 276 plasma proteins were analyzed using Olink® panels, with biomarkers identified through ordinal logistic regression, random forest (RF) analysis and the Boruta algorithm. Results The discovery cohort included 60 participants, with 60% having fibrosis stage F0–1 and 40% having F2-4. The validation cohort had 59 participants, of whom 35 had fibrosis stage F0-1 (59.3%) and 24 had stage F2-4 (40.7%). Five biomarkers were significantly associated with fibrosis stage in the discovery cohort, with four confirmed in the validation cohort. A model combining angiotensin converting enzyme-2 (ACE2), hepatocyte growth factor (HGF) and insulin-like growth factor-binding protein-7 (IGFBP-7) demonstrated strong predictive performance for significant fibrosis (c-statistics 0.82–0.83), outperforming fibrosis-4 (FIB-4) (c-statistics 0.61–0.72). Conclusions A biomarker model including ACE2, HGF and IGFBP7 shows promise in distinguishing between low-stage and significant fibrosis.

Plasma Insulin-Like Growth Factor-Binding Protein-2 Levels Predict Severe Septic Acute Kidney Injury: A Mendelian Randomization Analysis.

Sepsis-associated acute kidney injury (SA-AKI) currently lacks highly sensitive biomarkers for early detection, resulting in delayed identification and intervention during its early stages and an independent risk of death. This study aimed to investigate the relationship between insulin-like growth factor-binding protein-2 (IGFBP-2) levels and the occurrence of sepsis-induced kidney injury and to evaluate the causal relationship between the two through Mendelian randomization (MR) analysis. This study employed a single-center, prospective cohort design involving 79 sepsis patients from the Intensive Care Unit (ICU) at the First Affiliated Hospital of Xinjiang Medical University, Ürümqi, China. The patients were divided into two groups,the SA-AKI group and the non-SA-AKI group, on the basis of whether they developed SA-AKI. The primary endpoint was whether SA-AKI occurred within 48 hours of admission. MR and sensitivity analyses were conducted to explore the causal relationships. The IGFBP-2 level had high diagnostic value for the prediction of SA-AKI. Receiver operating characteristic (ROC) curve analysis revealed that IGFBP-2 alone predicted SA-AKI, with an area under the curve (AUC) of 0.8994, a cut-off value of 709.004, a sensitivity of 88.64%, and a specificity of 85.71%. The combined prediction of the IGFBP-2 score, acute physiology and chronic health evaluation (APACHE) II score, sequential organ failure assessment (SOFA) score, and use of vasopressors had an AUC of 0.9604, a sensitivity of 93.18%, and a specificity of 82.86%. MR analysis revealed no causal relationship between genetically predicted IGFBP-2 levels and AKI (OR: 1.1507, 95% CI:0.88-1.50, p = 0.2995). Plasma IGFBP-2 levels can predict the occurrence of SA-AKI in sepsis patients. However, MR analysis suggests that there is no direct causal relationship between plasma IGFBP-2 levels and septic kidney injury, and the underlying mechanisms need to be further investigated in randomized controlled trials.

Urinary [TIMP-2]•[IGFBP7], TIMP-2, IGFBP7, NGAL, and L-FABP for the prediction of acute kidney injury following cardiovascular surgery in Japanese patients.

Acute kidney injury (AKI) following cardiac surgery is common and is associated with poor outcomes. The combination of urinary tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) is a strong predictor of AKI after cardiac surgery. However, most studies have focused on non-Asian populations, and comparisons with other AKI biomarkers or the optimal timing for measurement have yet to be explored. We prospectively enrolled adult patients at Kochi Medical School Hospital in Kochi, Japan, to assess the predictive values of [TIMP-2]•[IGFBP7], TIMP-2, IGFBP7, neutrophil gelatinase-associated lipocalin (NGAL), and liver fatty acid-binding protein (L-FABP) measured preoperatively and at 2, 4, 6, and 8h, as well as on day 1 and day 2 after postoperative intensive care unit (ICU) admission, using receiver operating characteristic curve (ROC) analysis. Of the 38 patients, 13 (34.2%) developed AKI: seven (18.4%) with stage 1, four (10.5%) with stage 2, and two (5.2%) with stage 3. ROC analysis showed that the area under the curve (AUC) for predicting any stage of AKI peaked at 0-4h, with the highest value at 2h after ICU admission. Among the biomarkers, [TIMP-2]•[IGFBP7] showed the best AUC at 2h after ICU admission, followed by TIMP-2, IGFBP7, L-FABP, and NGAL. Our study demonstrated the good predictive performance of urine biomarkers, including [TIMP-2]•[IGFBP7], TIMP-2, IGFBP7, NGAL, and L-FABP, for any stage of cardiac surgery-associated AKI (CSA-AKI). The combination of TIMP-2 and IGFBP7 measured 2h after postoperative ICU admission effectively predicted CSA-AKI, identifying patients at higher risk.

Associations of circulating insulin-like growth factor-1 and insulin-like growth factor binding protein-3 with the expression of stem cell markers in benign breast tissue

Abstract Background The insulin-like growth factor (IGF) pathway is implicated in a naturally occurring process of tissue remodeling during which cells acquire stem cell-like characteristics. We examined associations of circulating IGF-1 and IGF binding protein-3 (IGFBP-3) with expression of CD44, CD24, and ALDH1A1 stem cell markers in benign breast biopsies. Methods This study included 151 cancer-free women with incident biopsy-confirmed benign breast disease and blood samples within the Nurses’ Health Study II. The data on reproductive and other BCa risk factors were obtained from biennial questionnaires. Immunohistochemistry (IHC) was done on tissue microarrays. For each core, the IHC expression was assessed using QuPath, and expressed as % of cells that stain positively for a specific marker out of the total cell count. Generalized linear regression was used to examine the associations of plasma IGF-I and IGFBP-3 (continuous log-transformed and quartiles) with log-transformed expression of each marker (in epithelium and stroma), adjusted for BCa risk factors. Results In multivariate analysis, continuous circulating IGF-1 and IGFBP-3 measures were not associated with the continuous expression of any of the markers in the epithelium or stroma. Women whose IGFBP-3 levels were in the top quartile appeared to have lower expression of stromal CD24 compared to those in the lowest quartile (β = − 0.38, 95% CI − 0.69, − 0.08, p-trend = 0.06). Conclusions Higher circulating IGFBP-3 levels were associated with lower stromal CD24 expression in benign breast tissue. Our findings provide indirect evidence of the inducing effect of IGF pathway on epithelial-to-mesenchymal transitions and stem cell activity in the breast.

The role of IGFBP-1 in the clinical prognosis and pathophysiology of acute kidney injury.

The ability to predict progression to severe acute kidney injury (AKI) remains an unmet challenge. Contributing to the inability to predict the course of AKI is a void of understanding of the pathophysiological mechanisms of AKI. The identification of novel prognostic biomarkers could both predict patient outcomes and unravel the molecular mechanisms of AKI. We performed a multicenter retrospective observational study from a cohort of patients following cardiac surgery. We identified novel urinary prognostic biomarkers of severe AKI among subjects with early AKI. Of 2,065 proteins identified in the discovery cohort, insulin-like growth factor binding protein 1 (IGFBP-1) was the most promising. We validated IGFBP-1 as a prognostic biomarker of AKI in 213 patients. In addition, we investigated its role in the pathophysiology of AKI using a murine model of cisplatin-induced AKI (CIAKI). Urinary IGFBP-1 concentration in samples collected from patients with stage 1 AKI following cardiothoracic surgery was significantly higher in patients who progressed to severe AKI compared with patients who did not progress beyond stage 1 AKI (40.28 ng/ml vs. 2.8 ng/ml, P < 0.0001) and predicted the progression to the composite outcome (area under the curve: 0.85, P < 0.0001). IGFBP-1 knockout mice showed less renal injury, cell death, and apoptosis following CIAKI, possibly through increased activation of the insulin growth factor receptor 1. IGFBP-1 is a clinical prognostic biomarker of AKI and a direct mediator of the pathophysiology of AKI. Therapies that target the IGFBP-1 pathways may help alleviate the severity of AKI.NEW & NOTEWORTHY The ability to predict progression to severe AKI remains an unmet challenge. Early prognostic biomarkers of AKI hold promise to improve patient outcomes by early implementation of clinical therapy, as well as unravel the pathophysiological mechanisms of AKI. Here, we present a novel urinary biomarker, IGFBP-1, that predicts the progression to severe AKI following cardiac surgery. In addition, we show that IGFBP-1 mice are protected against CIAKI, suggesting a mechanistic role for IGFBP-1 in AKI.

Novel Biomarkers for Early Detection of Acute Kidney Injury: A Multi-center Prospective Study

Background: Acute kidney injury (AKI) is a common and serious clinical condition associated with high morbidity, mortality, and healthcare costs. Traditional diagnostic markers such as serum creatinine and urine output demonstrate limited sensitivity and specificity for early AKI detection, delaying diagnosis and potentially missing the therapeutic window for effective intervention. This study aimed to evaluate the performance of novel biomarkers, individually and in combination, for early AKI detection across diverse clinical settings. Methods: In this prospective multi-center study, we enrolled 60 adult patients at risk for developing AKI, stratified across four common clinical scenarios: cardiac surgery (n=15), contrast-induced nephropathy (n=15), sepsis-associated AKI (n=15), and nephrotoxic medication exposure (n=15). Seven urinary and plasma biomarkers were measured at enrollment and at multiple timepoints (6h, 12h, 24h, 48h, 72h): neutrophil gelatinase-associated lipocalin (NGAL) in urine and plasma, kidney injury molecule-1 (KIM-1), interleukin-18 (IL-18), tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) product, liver-type fatty acid-binding protein (L-FABP), and cystatin C. AKI was defined according to KDIGO criteria. Biomarker performance was assessed using receiver operating characteristic (ROC) curves, and multivariable models were developed to evaluate biomarker combinations. Results: Of the 60 patients, 26 (43.3%) developed AKI within 7 days, with a median time from enrollment to AKI diagnosis of 33.5 hours. At the 6-hour timepoint, urinary TIMP-2×IGFBP7 demonstrated the highest discriminative capacity for AKI prediction (AUC-ROC 0.85, 95% CI 0.76-0.94), followed by urinary NGAL (AUC-ROC 0.83, 95% CI 0.73-0.93) and plasma cystatin C (AUC-ROC 0.81, 95% CI 0.70-0.92). The combination of these three biomarkers significantly improved diagnostic performance (AUC-ROC 0.92, 95% CI 0.85-0.99), and further enhancement was achieved by integrating them with clinical risk factors (AUC-ROC 0.94, 95% CI 0.88-1.00). Distinct biomarker patterns emerged across different AKI etiologies: urinary NGAL performed best in sepsis-associated AKI (AUC-ROC 0.91), KIM-1 in contrast-induced nephropathy (AUC-ROC 0.85), and TIMP-2×IGFBP7 performed consistently well across all etiologies. All biomarkers demonstrated significant positive correlations with AKI severity and were independently associated with increased in-hospital mortality and hospital length of stay. Conclusions: Novel biomarkers, particularly TIMP-2×IGFBP7, urinary NGAL, and plasma cystatin C, can detect AKI significantly earlier than conventional markers across diverse clinical settings. The combination of multiple biomarkers substantially improves diagnostic accuracy, and distinct biomarker patterns emerge across different AKI etiologies. These findings suggest that biomarker panels may enhance early AKI detection, potentially enabling earlier intervention and improved patient outcomes.

Editor's Note to: “p53-Dependent and p53-Independent Induction of Insulin-Like Growth Factor Binding Protein-3 by Deoxyribonucleic Acid Damage and Hypoxia”

Editor's Note to: “p53-Dependent and p53-Independent Induction of Insulin-Like Growth Factor Binding Protein-3 by Deoxyribonucleic Acid Damage and Hypoxia”

Urine TIMP2.IGFBP7 Reflects Kidney Injury After Moderate Volume Paracentesis in Patients With Ascites: A Randomized Control Study.

Urinary biomarkers may predict acute kidney injury (AKI) in cirrhosis with ascites in a moderate volume paracentesis setting. The study aimed to assess the risk and consequence of AKI and its progression in patients with decompensated cirrhosis undergoing paracentesis using a urine test measuring tissue inhibitor of metalloproteinases-2 (TIMP2) and insulin-like growth factor-binding protein 7 (IGFBP7). A randomized, controlled trial was performed. All outpatients with decompensated cirrhosis with ascites and diuretic complications were enrolled and randomized into 3 and 5 L paracentesis groups. Serial urine samples were analyzed for TIMP2. IGFBP7 concentration before and after paracentesis. A total of 90 patients with decompensated cirrhosis were consecutively enrolled during the study period. After screening, 29 patients were enrolled in the 3-L paracentesis group, and 25 patients were enrolled in the 5-L paracentesis group. The mean of the MELD score was 8 ± 1.2. Urine TIMP2.IGFBP7 > 2, rising urine TIMP2, and rising urine TIMP2/urine Cr were shown in patients within the 5-L group for 48% (p = 0.015), 32% (p = 0.049), and 76% (p = 0.010) respectively, indicating a higher incidence of renal tubular injury markers in this group. Urine TIMP2.IGFBP7/1000 > 2 was statistically significant to predict a hemodynamic event (p = 0.002). In cirrhotic patients with ascites undergoing paracentesis, a 5-L paracentesis volume was associated with a higher incidence of renal tubular injury markers. Trail Registration: The national clinical registration number was TCTR20191116003.